Chiauranib for treatment of small cell lung cancer

ABSTRACT

Disclosed are a method for treating small cell lung cancer by using chiauranib and the use of chiauranib in the preparation of a drug for treating small cell lung cancer.

This application claims the priority of Chinese Patent Application No.201910229379.6, filed with the China National Intellectual PropertyAdministration on Mar. 25, 2019, and titled with “CHIAURANIB FORTREATMENT OF SMALL CELL LUNG CANCER”, and the disclosures of which arehereby incorporated by reference in its entirety.

FIELD

The present disclosure relates to the technical field ofpharmaceuticals, specifically to use of the compound chiauranib in thetreatment of small cell lung cancer.

BACKGROUND

Both the incidence and mortality of lung cancer rank first amongmalignant tumors. Small cell lung cancer (SCLC) accounts for 10%˜15% ofthe total number of lung cancers. Its clinical characteristics andbiological behavior are different from other types of lung cancer, whichare reflected in the short doubling time, metastasis in early stages,and extremely high degree of malignancy. Untreated patients often diewithin 2˜4 months. Although newly-treated patients are more sensitive tochemotherapy, they are prone to drug resistance and relapse, and arerelatively insensitive to second-line chemotherapy drugs, and theprognosis is poor. 30%˜40% of the patients diagnosed are in the limitedstage, and 60%˜70% of the patients are in the extensive stage. Thelong-term survival rate of the limited stage is 20%, and that of theextensive stage is only 2%.

Etoposide/cisplatin regimen (EP regimen) is currently the mainchemotherapy regimen for SCLC. The results of a phase III clinical studyshowed that in patients with limited-stage SCLC, the 2-year and 5-yearsurvival rates of EP regimen were better than that of thecyclophosphamide/epirubicin/vincristine regimen (25% vs. 10%, 8% vs.3%); for patients with extensive-stage SCLC, the EP regimen can alsobring survival benefits. A series of subsequent studies have alsoconfirmed the effectiveness of the EP regimen, so the EP regimen hasbecome the standard first-line chemotherapy regimen for SCLC.

Irinotecan/cisplatin (CPT-11/DDP) (IP regimen) is another conventionalchemotherapy regimen for the treatment of SCLC. In a controlled study,the IP regimen group and the EP regimen group were set up at the sametime. The results showed that the objective response rates (ORR) ofpatients in the two groups were 84.4% and 67.5%, respectively (P=0.02),and the median survival time was 12.8 months and 9.4 months,respectively (P=0.002).

In addition to the above-mentioned conventional EP and IP regimens,there are also a few second-line treatment regimens, such as combinationtherapy with topotecan or paclitaxel. Studies have shown that theoverall survival, quality of life and improvement of symptoms in thebest supportive treatment group combined with topotecan aresignificantly better than those in the best supportive treatment groupalone. Therefore, topotecan has become the second-line chemotherapeuticdrug for SCLC.

Despite the existence of the above treatment options, in general, SCLCstill lacks effective treatment methods. After the failure ofconventional EP or IP regimens, there are fewer second-line options(such as topotecan, paclitaxel, etc.), and after the failure ofsecond-line treatment, guidelines such as NCCN only recommend supportivetreatment or clinical research, lacking available treatment options atthis time. In addition, whether it is the EP regimen or the IP regimen,the toxicity of cisplatin often inhibits its efficacy, which may affectthe treatment due to patient tolerance. Therefore, for small cell lungcancer, there is still a need to explore treatment options with betterefficacy and/or fewer adverse reactions.

SUMMARY

In view of this, the purpose of the present disclosure is to provide atreatment option with better efficacy and/or fewer adverse reactions forsmall cell lung cancer. The inventors unexpectedly discovered in theresearch that the compound of formula (I) (having a chemical name ofN-(2-aminophenyl)-6-(7-methoxyquinoline-4-oxo)-1-naphthylamide, and acommon name of chiauranib) can effectively treat small cell lung cancer,and has a satisfactory clinical benefit rate for small cell lung cancer,with an antitumor activity relatively significantly superior to othertypes of tumors such as non-small cell lung cancer and colon cancer.

Therefore, in one aspect of the present disclosure, use of chiauranib inthe manufacture of a medicament for treating small cell lung cancer isprovided.

Correspondingly, the present disclosure also provides a method fortreating small cell lung cancer, comprising administering chiauranib toa subject in need thereof.

In the above-mentioned pharmaceutical use and treatment method of thepresent disclosure, chiauranib can also be used in combination with anadditional active pharmaceutical ingredient.

In some preferred embodiments of the present disclosure, the small celllung cancer is recurrent or refractory small cell lung cancer.

The recurrent or refractory small cell lung cancer refers to the diseaseprogression or recurrence of small cell lung cancer after receiving oneor two or more different treatments, especially systemic chemotherapyregimens (such as platinum-containing chemotherapy regimens).

Chiauranib is a small molecule anti-tumor targeted drug targetingmultiple protein kinases. However, there is no report on the use ofchiauranib against small cell lung cancer.

We conducted a phase I clinical trial of chiauranib for patients withadvanced solid tumors, enrolling a total of 18 patients with 8 types oftumor indications, including colorectal cancer, non-small cell lungcancer, gastric cancer, ovarian cancer, thyroid papillary carcinoma,diffuse large B-cell lymphoma, fibrosarcoma, and poorly differentiatedrenal carcinoma. The results showed that no objective remission wasobserved for the main clinical efficacy indicators, including cases ofcomplete remission (CR) and partial remission (PR).

We also conducted a phase Ib clinical trial of Chiauranib for recurrentand/or refractory small cell lung cancer, enrolling 25 patients withsmall cell lung cancer, including 20 patients with efficacy evaluation.The results showed that the best efficacy evaluation in 4 patients wasPR, and the objective response rate (ORR) was 20%. Considering thedifficulty of treatment of small cell lung cancer, such treatmentresults are quite encouraging.

The above-mentioned experimental results show that in clinical trials ofchiauranib for 8 types of tumors including non-small cell lung cancerand colon cancer, no patients with objective remission were observed forthe main clinical efficacy indicators. However, chiauranib showed goodefficacy in clinical trials of small cell lung cancer, with an objectiveresponse rate (ORR) of 20%, indicating that small cell lung cancer is aneffective tumor indication for chiauranib. Compared with the efficacy onother types of tumors, the efficacy of chiauranib on small cell lungcancer is unexpected.

Based on the above findings, the present disclosure proposes theapplication of chiauranib in patients with small cell lung cancer,including but not limited to treatment of the administration ofchiauranib alone, treatment of chiauranib in combination with anadditional drug or adjuvant drug or therapeutic agent, as well astreatment of chiauranib in combination with other treatment(s) (such assurgery, radiotherapy, etc.).

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows a waterfall plot of the efficacy of chiauranib on varioustumors in the phase I clinical study;

FIG. 2 shows a waterfall plot of the efficacy of chiauranib on smallcell lung cancer in a phase Ib clinical study.

DETAILED DESCRIPTION

The present disclosure discloses use of chiauranib in the treatment ofsmall cell lung cancer. Those skilled in the art can learn from thecontents of the present disclosure and appropriately improve the processparameters. It should be particularly pointed out that all suchalternatives and modifications are obvious to those skilled in the artand are considered to be included in the present disclosure. Theapplications of the present disclosure have been described by preferredexamples, and apparently, those skilled in the art can make alternationsor suitable modifications and combinations to the applications asdescribed herein to achieve and apply the technology of the presentdisclosure without departing from the content, spirit and scope thereof.

In the present disclosure, chiauranib can be used in its prototypecompound or salt form (pharmaceutically acceptable salt). Thepharmaceutically acceptable salt can be prepared by using, for example,the following inorganic or organic acids: hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolicacid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaricacid, fumaric acid, malic acid, mandelic acid, tartaric acid, citricacid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid,benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid,salicylic acid, methanesulfonic acid, benzenesulfonic acid ortoluenesulfonic acid.

The pharmaceutically acceptable salt of the present disclosure can beprepared by conventional methods, for example, by dissolving thecompound of the present disclosure in a water-miscible organic solvent(such as acetone, methanol, ethanol, and acetonitrile), and adding anexcessive amount of aqueous solution of organic acid or inorganic acidto precipitate the salt from the resulting mixture, from which thesolvent and the remaining free acid are removed, and then theprecipitated salt can be separated.

Chiauranib or a pharmaceutically acceptable salt thereof of the presentdisclosure may include a solvate form, and preferably, the solvate is ahydrate.

In the treatment of chiauranib combined with an additional therapeuticdrug, the additional therapeutic drug means that it has an effect on thetreatment or prevention of cancer, including any compound or componentcapable of ameliorating, reducing, regulating, improving or eliminatingthe cause of disease, or improving symptoms, or contributing to theoverall efficacy of the patient.

In the therapeutic application of the present disclosure, theadministration dose of chiauranib may be 1 mg to 500 mg per day, such as1 mg to 100 mg per day, preferably 5 mg to 80 mg per day, 5 mg to 70 mgper day, 5 mg to 60 mg per day or 5 mg to 50 mg per day, and morepreferably, the daily dose may be, for example, 1 mg, 2 mg, 3 mg, 4 mg,5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mgper day. The specific application dose can be adjusted according to theactual situation of the patient, the treatment regimen and thecombination with other drugs.

In the therapeutic application of the present disclosure, chiauranib canbe administered to a subject in a form of any suitable pharmaceuticalcomposition. The pharmaceutical composition may be a dosage form such asoral administration or parenteral administration (includingintramuscular, intravenous and subcutaneous routes), for example,capsule, tablet, granule, powder, syrup, emulsion, microemulsion,solution or suspension.

In the application of the combination therapy of the present disclosure,chiauranib and additional therapeutic agent can be administered to asubject to be treated separately, simultaneously or sequentially;chiauranib and the additional therapeutic agent can be present in thesame pharmaceutical composition, or they are administered separately inthe form of different pharmaceutical compositions (kits or medicineboxes). The use of chiauranib provided by the present disclosure will befurther explained below.

Example 1: Phase I Clinical Trial of Chiauranib in the Treatment ofPatients with Advanced Solid Tumors

Test drug: chiauranib capsules, strength: 5 mg, 25 mg, produced byShenzhen Chipscreen Biosciences, Co., Ltd.

Dosage regimen: The starting dose was 10 mg/day. After the startingdose, according to the modified Fibonacci method, the patients wereenrolled in order from low dose to high dose, and the set dose groupswere 20 mg, 35 mg, 50 mg, 65 mg . . . dose groups, respectively, untilthe MTD was determined.

Chiauranib capsules were administered orally, once a day in the morning.Before knowing the analysis data of the effects of food onbioavailability, the drugs were administered on empty stomach.

Number of cases: 18 cases were enrolled.

Inclusion Criteria:

1. Patients with advanced solid tumors that had been clearly diagnosedby histology or cytology, including non-small cell lung cancer,colorectal cancer, ovarian cancer, renal cell carcinoma,gastrointestinal stromal tumor, gastric cancer, etc.;

2. Patients who had failed the standard treatment regimen or lacked thestandard treatment regimen;

3. Body mass index: in the range of 18-28;

4. Age: 18˜65 years old, no gender limit;

5. ECOG score: 0 or 1 point;

6. The functions of major organs met the following standards:

a) Routine blood examination: hemoglobin (Hb)≥100 g/L (no bloodtransfusion within 14 days); absolute neutrophil count (ANC)≥1.5×10⁹/L;platelet (PLT)≥100×10⁹/L;

b) Biochemical examination: serum creatinine Cr≤upper limit of thenormal value (ULN); bilirubin (BIL)≤1.25×ULN; alanine aminotransferase(ALT), aspartate aminotransferase (AST)≤1.5×ULN; fasting triglycerides(TG)≤3.0 mmol/L, and fasting total cholesterol (TC)≤7.75 mmol/L;

c) Coagulation function: International normalized ratio (INR)<1.5.

7. For women, contraceptive measures were required during the studyperiod and within 6 months after the end of the study, the serum orurine pregnancy test was negative within 7 days before they wereenrolled, and they must be non-lactating patients; and for men,contraceptive measures were required during the study period and within6 months after the end of the study;

8. Having voluntarily signed written informed consent form.

Treatment Plan:

The prescribed dose of Chiauranib capsules was administered orally onempty stomach once every day, and every 28 days was a treatment cycle;there was no stopping interval during the treatment cycles, and allenrolled patients received the test drug treatment until the diseaseprogressed or intolerable toxicity appeared.

Efficacy evaluation: The clinical benefits of tumor treatment include:

complete remission (CR)

partial remission (PR)

Judgment criteria: The efficacy was evaluated according to the RECISTversion 1.1 (2009) standard of solid tumors.

Safety assessment: physical examination, vital signs, ECOG physicalscore, blood routine, urine routine, 12-lead ECG, blood biochemistry,electrolytes, coagulation function, myocardial enzymes, troponin, TSH,FT3, FT4, amylase, echocardiography, 24-hour urine proteinquantification (if necessary), and adverse events were included.

Clinical Trial Results:

A total of 18 patients were enrolled in the trial, all of which wereincluded in the FAS, SS, and PPS analysis sets. Among the 18 patients, 7cases (38.9%) had colorectal cancer, 5 cases (27.8%) had non-small celllung cancer, and 1 case each for gastric cancer, ovarian cancer, thyroidpapillary carcinoma, diffuse large B-cell lymphoma, fibrosarcoma, andpoorly differentiated renal carcinoma.

The results showed that no cases with objective remission were observedfor the main clinical efficacy indicators, and the objective remissionsincluded complete remission (CR) and partial remission (PR).

Example 2: Phase Ib Clinical Trial of Chiauranib Alone in the Treatmentof Recurrent and Refractory Small Cell Lung Cancer

Test drug: Chiauranib capsules, strength: 5 mg, 25 mg, produced byShenzhen Chipscreen Biosciences, Co., Ltd.

Dosage regimen: Chiauranib capsules were administered at 50 mg/day, QD(no adjustments to body weight or body surface area), on an emptystomach every morning with water, swallowing whole capsules intact.Continuous administration for 28 days constituted a treatment cycle, andthere was no interval between treatment cycles.

Number of cases: 25 cases were enrolled.

Inclusion Criteria:

1. Age: ≥18 years old and ≤75 years old, no gender limit;

2. Patients with small cell lung cancer confirmed by histology orcytology;

3. The disease had progressed or recurred after receiving at least 2different systemic chemotherapy regimens (including platinum-containingchemotherapy regimens) in the past;

4. According to the RECIST1.1 standard, there was at least onemeasurable target lesion, and the lesions treated by radiotherapy orlocal area treatment must have imaging evidence of disease progressionbefore they can be regarded as target lesions;

5. ECOG physical score: 0-1 point;

6. The functions of major organs met the following standards:

a) Blood routine: absolute neutrophil count≥1.5×10⁹/L,platelet≥75×10⁹/L, hemoglobin≥80 g/L;

b) Blood biochemistry: total bilirubin≤1.5 times the upper limit of thenormal value, AST/ALT≤2.5 times the upper limit of the normal value (forliver metastasis, ≤5 times the upper limit of the normal value), serumcreatinine≤1.5 times the upper limit of the normal value;

Coagulation function: Prothrombin time-international normalized ratio(PT-INR)<1.5.

7. Expected survival time ≥3 months;

8. Having voluntarily signed written informed consent form.

Treatment Plan:

The test subjects were administered with 50 mg of Chiauranib capsulesorally once a day, every 28 days as a treatment cycle, and there was nostopping interval during the treatment cycles. Throughout the trialperiod, all subjects continued treatment until any of the followingconditions (whichever occurred first) occurred: disease progression,intolerable toxic response, death, withdrawal of informed consent, orloss to follow-up.

Efficacy evaluation: According to the RECIST1.1 standard, evaluation wasperformed in the baseline period and at the 4th weekend after treatment,and repeated every 8 weeks until the disease progressed. Tumor imagingexaminations include CT or MRI of the neck, chest, whole abdomen, andpelvis. Examinations of other parts were carried out when necessarybased on clinical indications. The same techniques and methods should beemployed for the baseline of the lesion and follow-up assessment andmeasurement.

Safety assessment: physical examination, vital signs, ECOG fitnessscore, blood routine, urine routine, 12-lead ECG blood biochemistry,electrolytes, coagulation function, myocardial enzymes, troponin, TSH,FT3, FT4, amylase, echocardiography, 24-hour urine proteinquantification (if necessary), and adverse events were included.

Clinical Trial Results:

25 patients with small cell lung cancer were enrolled in stages,including 20 patients with efficacy evaluation. The results showed thatthe best efficacy evaluation in 4 patients was PR, and the objectiveresponse rate (ORR) was 20%. These results show that Chiauranib can beeffectively used in the treatment of small cell lung cancer.

Example 3: Comparison of the Efficacy of Chiauranib in the Treatment ofSmall Cell Lung Cancer and Other Tumors

FIG. 1 shows a waterfall plot of the efficacy of Chiauranib on varioustumors in the phase I clinical study, including 15 patients withmeasurable lesions among the 18 patients enrolled. The tumor typesincluded were colorectal cancer, non-small cell lung cancer, gastriccancer, ovarian cancer, thyroid papillary carcinoma, and poorlydifferentiated renal carcinoma. After treatment, there were no patientswhose target lesions were reduced by more than 30% from baseline, andthe target lesions were reduced by 30% from baseline is a standard forclinical objective remission of tumor treatment.

FIG. 2 shows a waterfall plot of the efficacy of Chiauranib on smallcell lung cancer in a phase Ib clinical study, including 20 patientswith efficacy evaluation among the 25 patients enrolled. Aftertreatment, there were 5 patients (25%) whose target lesions were reducedby more than 30% from baseline, of which 4 patients were evaluated aspartial remission (PR) in clinical efficacy.

The following table shows the comparison of the efficacy of Chiauranibin the treatment of small cell lung cancer and other tumors. Chiauranibhas obvious advantages in the treatment of small cell lung cancer overother tumors in terms of efficacy indicators such as objectiveremission, clinical benefit, and reduction of target lesions.

Comparison items Phase I clinical study Phase Ib clinical study Tumortypes 8 common tumors Small cell lung cancer Number of patients 18 20evaluated PR (%) 0 4 (20) Target lesion reduced 0 5 (25) by more than30%

The above description is only preferable embodiments of the presentdisclosure. It should be noted that those skilled in the art can makeimprovements and modifications without departing from the principle ofthe present disclosure. These improvements and modifications should alsofall within the protection scope of the present disclosure.

1. Use of chiauranib represented by the compound of formula (I) in themanufacture of a medicament for treating small cell lung cancer,


2. Use of the combination of chiauranib represented by the compound offormula (I) according to claim 1 and an additional active pharmaceuticalcompound in the manufacture of a medicament for treating small cell lungcancer.
 3. A method for treating small cell lung cancer, comprisingadministering chiauranib represented by the compound of formula (I)according to claim 1 to a subject in need thereof.
 4. The methodaccording to claim 3, further comprising administering an additionaltherapeutic drug to the subject.